High precision manufacture of polyurethane products such as spinal disc implants having a gradual modulus variation

ABSTRACT

A process for making a polymeric product having a gradual variation in modulus through at least a portion of the product is disclosed together with an artificial spinal disc formed using the process.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of and priority to PCTApplication No. PCT/GB2003/004352 filed on Oct. 8, 2003 claimingpriority from British Patent Application No. 0223327.8 filed on Oct. 8,2002, the entire contents of each of which are incorporated herein byreference.

The present invention relates to a method of manufacturing a polymericproduct and to a product for medical use made in accordance with themethod. An example of a component made from the material and using themethod of the invention is an artificial spinal disc or disc spacer usedto replace a displaced or damaged intervertebral disc in the spine of apatient although the invention is also applicable to the manufacture ofreplacement joints in addition to other surgical instrumentation andcomponents for the healthcare industry.

Although reference will now be made primarily to the application of theinvention in the manufacture of an artificial spinal disc, the inventionis not limited to an artificial spinal disc or the specific method ofmaking such a disc, as has already been mentioned above.

Approximately one third to a quarter of the length of an adult humanspine is occupied by the vertebral discs. Each disc comprises an annularwall (annulus fibrosus) that surrounds and contains a central nucleus(nucleus pulposus) filled with gelatinous material that occupiesapproximately 30 to 50% of the cross sectional area of the disc. Theannular wall is a concentrically laminated structure containing alignedcollagen fibres and fibrocartilage and provides the major stabilizingstructure to resist torsional and bending forces applied to the disc.The discs are contained between vertebral endplates comprised of hyalinecartilage that act as an intermediate layer between the hard vertebraeand the softer material of the disc.

The joints and musculoskeletal tissues of the human body are subject totraumatic injury and disease and degenerative processes that over aperiod of time can lead to the deterioration or failure of the jointcausing severe pain or immobility. Generally, the ability of a loadbearing joint to provide pain free articulation and carry load isdependent upon the presence of healthy bone, cartilage and associatedmusculoskeletal tissues that provide a stable joint With reference tothe spine, spinal disc degeneration, characterised by features such asloss of fluid, annular tears and myxomatous changes can result indiscogenic pain and/or disc bulging or herniation of the nucleus inwhich the disc protrudes into an invertebral foramen comprising spinalnerves resulting in back pain and/or sciatica. This condition is morecommonly referred to as a “slipped” disc.

To alleviate the condition described above, the damaged spinal disc maybe surgically removed from the spine and the two adjacent vertebraeeither side of the damaged disc fused together (arthrodesis). Althoughthis technique successfully eliminates the symptoms of pain anddiscomfort and improves joint stability, it results in a total loss ofmovement of the fused vertebral joint and increases the stress placed onthe adjacent joints leading to collateral damage of these joints andassociated soft tissues. The degenerative cycle then begins anew.

A more desirable solution is to replace the damaged spinal disc with anartificial implant (arthroplasty) that allows full, pain free movementof the vertebrae and which mimics the function of a healthy spinal disc.Artificial spinal discs currently exist for use in such a procedure.However, the development of existing artificial discs has been limited,despite advances in biomaterials, because they lack the complexity ofstructure and cannot adequately mimic the biomechanics of a normalhealthy human spinal disc.

Conventional artificial discs articulate using a bearing surfacemanufactured using metals, alloys or durable polymers includingultra-high molecular weight polyethylene. However, the use of hard,non-deformable bearing surfaces render the implant non-compliant andunable to replicate the compliant load bearing capacity provided by thenatural disc. As a result, adjacent spinal levels are still exposed toincreased mechanical stresses resulting in a high risk of furtherdegeneration.

Compliant artificial spinal discs are generally either manufacturedusing a material of single uniform hardness (single durometer) or usingtwo materials of differing hardness (dual durometer), in which case thematerial has a lower modulus core contained within a higher modulusshell. The former requires a compromise in material specification tobalance strength and wear resistance with compliance whereas the latteroften generates problems caused by a progressive failure along theinterface between the two materials over a period of use. An artificialspinal disc of the latter type is known from U.S. Pat. No. 5,171,281.

A need therefore remains for an artificial spinal disc implant which canbe surgically inserted in place of a damaged spinal disc and which willenable full, pain-free movement of the affected vertebral joint, whichis durable enough to withstand the loads and wear imposed upon it in usewithout failing, and at the same time exhibit biomechanics which are assimilar as possible to that of the body's own natural spinal discs andso can withstand both compression and torsional loading. If theserequirements are not adequately met, and the artificial disc is toostiff, it will not deform sufficiently during movement and excessivedeformation of the adjacent natural discs will occur. On the contrary,if the disc does not have the required degree of stiffness, excessivemovement of the disc will occur causing it to bulge out resulting inpain and discomfort for the patient.

SUMMARY

According to an aspect of the invention, there is provided a process formaking a polymeric product having a gradual variation in modulus throughat least a portion of the product, comprising the steps of:

(a) reacting a multifunctional isocyanate, a polyol and, optionally, achain extender, wherein at least two reagents selected from theisocyanate, the polyol, the chain extender, any mixture thereof and anypre-polymer formed therefrom, are intensively mixed to form a firstpolyurethane having a predetermined stoichiometry and thermal history;(b) reacting a multifunctional isocyanate, a polyol and, optionally, achain extender, wherein at least two reagents selected from theisocyanate, the polyol, the chain extender, any mixture thereof and anypre-polymer formed therefrom, are intensively mixed to form a secondpolyurethane having a predetermined stoichiometry and thermal historywhich is different to the stoichiometry and thermal history of the firstpolyurethane; and(c) injecting the first and second polyurethanes into a mould definingthe polymeric product before the polymerisation reactions associatedwith the production of the first and second polyurethanes are completeso that polymerisation reactions between the first and secondpolyurethanes occur in the mould.

Although reference is made to first and second polyurethanes, it will beappreciated that the invention also includes within its scope a processinvolving more than two polyurethanes, each of which has a differentpredetermined stoichiometry and thermal history.

The modulus referred to is the modulus of elasticity or tensile modulus,also referred to as Young's Modulus, and is the ratio of stress tostrain below the elastic limit. The Young's Modulus is calculated bydividing the strain into stress and provides a measure of the stiffnessof the material.

The process preferably involves the step of injecting the first andsecond polyurethanes into the mould simultaneously. The polyurethanesmay be injected at the same rate into the mould or, the relative rate ofinjection of the two polyurethanes into the mould may be altered so thatmore of one polyurethane is injected into the mould than the other thusproviding a material that exhibits a graduation in modulus.

In one embodiment, the process includes the step of mixing the first andsecond polyurethanes prior to injection into the mould via a commoninjection port. Even when the polyurethanes are mixed prior toinjection, it is possible to vary the relative rates of injection byvarying the rate of delivery of each polyurethane.

Advantageously, the length of the common injection port may be alteredto control the degree of interfacial mixing of the first and secondpolyurethanes prior to injection into the mould.

In one embodiment, the first and second polyurethanes may be formedsimultaneously in separate apparatus. In this method, known as the dualhead technique, two output streams, having different compositions, fromtwo PPM machines (described in more detail below) are fed to a mouldwith two separate inputs at the same time. The input ports of the mouldare so arranged to cause the mould to fill in a prearranged manner sothat interfacial mixing of the two streams occurs resulting in theformation of a graded modulus structure. Alternatively, the two separatestreams may be mixed prior to injection into the mould in which casethey are injected through a common injection port.

A single PPM machine for producing the polyurethane may also be employedin which case the method includes the step of forming the firstpolyurethane, delivering it to an intermediate vessel and perturbing therelative amounts of the reagents being mixed by the machine to form thesecond polyurethane with a different stoichiometry.

The method may include the step of delivering the second polyurethane toan intermediate vessel.

The first and second polyurethanes are preferably injected into themould from said intermediate vessels simultaneously.

The process preferably includes the step of controlling the temperatureof each intermediate vessel to impart a known thermal history to thefirst and second polyurethanes contained therein.

According to another aspect of the invention, there is provided aprocess for making a polymeric product having a variable modulus throughat least a portion of the product comprising the steps of:

(a) reacting a multifunctional isocyanate, a polyol and, optionally, achain extender, wherein at least two reagents selected from theisocyanate, the polyol, the chain extender, any mixture thereof and anypre-polymer formed therefrom, are intensively mixed to form apolyurethane having a predetermined stoichiometry and thermal history;(b) perturbing the relative amounts of said at least two reagents duringthe course of the reaction to continuously vary the modulus of thepolyurethane so formed and,(c) injecting the polyurethane into a mould defining the polymericproduct before the polymerisation reactions associated with theproduction of the polyurethane is complete so that polymerisationcontinues in the mould.

The polyurethane may be passed through an extruder to be reactivelyextruded therein in the method according to either the first or secondaspects of the invention.

The polyurethane may advantageously undergo thermal profiling during thereactive extrusion step.

According to another aspect of the invention, there is provided anapparatus for making a polymeric product having a gradual variation inmodulus through at least a portion of the product comprising:

(a) a first delivery system for quantitatively dispensing at least tworeagents selected from an isocyanate, a polyol, a chain extender, anymixture thereof and any pre-polymer formed therefrom; mixing means forintensively mixing said at least two reagents to form a firstpolyurethane having a predetermined stoichiometry.(b) a second delivery system for quantitatively dispensing at least tworeagents selected from an isocyanate, a polyol, a chain extender, anymixture thereof and any pre-polymer formed therefrom; mixing means forintensively mixing said at least two reagents and reactive extrusionmeans to form a second polyurethane having a different predeterminedstoichiometry to that of the first polyurethane, and(c) means for injecting the first and second polyurethanes into a mouldbefore the polymerisation reactions associated with the formation of thefirst and second polyurethanes are complete so that polymerisationreactions between the first and second polyurethanes occur in the mould.

In one embodiment, the apparatus includes a common injection port forinjecting the first and second polyurethanes into the mouldsimultaneously.

The apparatus may also include means for varying the relative amounts ofthe first and second polyurethanes injected into the mould or, therelative rates of injection of the first and second polyurethanes intothe mould.

According to another aspect of the invention, there is provided anapparatus for making a polymeric product having a gradual variation inmodulus through at least a portion of the product comprising:

(a) a delivery system for quantitatively dispensing at least tworeagents selected from an isocyanate, a polyol, a chain extender, anymixture thereof and any pre-polymer formed therefrom; mixing means forintensively mixing said at least two reagents to form a firstpolyurethane having a predetermined stoichiometry.(b) an intermediate vessel into which the first polyurethane is directedwhilst the delivery system is used to quantitatively dispense at leasttwo reagents selected from an isocyanate, a polyol, a chain extender,any mixture thereof and any pre-polymer formed therefrom; mixing meansfor intensively mixing said at least two reagents and reactive extrusionmeans to form a second polyurethane having a different predeterminedstoichiometry to that of the first polyurethane, and(c) means for injecting the first and second polyurethanes into a mouldbefore the polymerisation reactions associated with the formation of thefirst and second polyurethanes are complete so that polymerisationreactions between the first and second polyurethanes occur in the mould.

In one embodiment, the apparatus includes a second intermediate vesselinto which the second polyurethane is directed so that the first andsecond polyurethanes are injected from their respective vessels into themould simultaneously. Alternatively, the first polyurethane is injectedinto the mould from an intermediate vessel and the second polyurethaneis injected into the mould directly from the delivery system.

The apparatus may include a mix head to mix the first and secondpolyurethanes prior to injection into the mould. The mix head may alsocomprise means for altering the rate of injection into the mould, orrate of mixing, of each of the polyurethanes.

According to another aspect of the invention, there is provided anartificial spinal disc comprising a solid body of polymeric materialthat exhibits at least a portion having a gradual variation in modulus.

In a preferred embodiment, the modulus varies substantially linearlythrough said portion.

The artificial spinal disc preferably comprises a nucleus surrounded byan annulus region, said portion being located in a region between thenucleus and annulus regions.

The invention also provides an artificial spinal disc manufacturedaccording to the process of the invention.

In one preferred embodiment for the manufacture of an artificial spinaldisc, the two-part mould has a retractable central portion, the centralportion being retracted after injection of polyurethane having a firststoichiometry and thermal history into the first part of the mould so asto form the annulus region so that the polyurethane having a secondstoichiometry and thermal history can be injected into the second partof said mould so that polymerisation reactions between the polyurethanesinjected into the first and second parts of the mould can occur in themould to form a region between the two polyurethanes that exhibit agradual variation in modulus.

The present invention also seeks to protect the use of the processaccording to the invention in the manufacture of an artificial spinaldisc or any surgical device or implant.

A method of manufacturing polyurethane having a high degree ofconsistency making them suitable for use in the medical product industryis known as precision polyurethane manufacture (PPM) and is described indetail in the Applicant's own earlier International Application No.PCT/GB01/03441 (Publication No. WO 02/11975), to which reference ishereby made.

The PPM process enables the reagent stoichiometry and thermal profile tobe controlled dynamically to reduce batch to batch property variationand WO 02/11975 specifically states that the reaction stoichiometry canbe controlled within 0.01-2%, preferably within 0.05-1%, and mostpreferably within 0.1-0.2% and that the thermal profile of the resultantpolyurethane can be controlled within 0.01-2° C., preferably within0.05-1° C., and most preferably within 0.1-0.5° C., preferably using acomputer. However, to date, no reference has been made to theapplication of the PPM process in the manufacture of a polymer productin which the reagent stoichiometry and thermal profile is purposivelyvaried so as to produce a polymer product which exhibits a gradualvariation in its modulus through the whole or part of that product.

In one embodiment, the polymer product comprises an artificial spinaldisc. The graduation in the modulus of the material provides anartificial disc having all the benefits of a dual material designwithout any of the problems associated with the bonding of twodissimilar, separate components. The disc contains and constrainsexcessive deformation whilst maintaining the normal physiologicalmotions of the spinal segment.

In a preferred embodiment, the artificial disc incorporates a set ofpolymeric end plates that exhibit a convex surface that engages with thesurface of an adjacent vertebral body. In this preferred embodiment, theend-plates are manufactured as part of the complete device. Therefore, aportion of the device exhibits a gradual change in modulus as a functionof distance from the surface of the body in an axial direction such thatthere are no interfacial bonds between the end-plates and the flexiblecote region of the spinal disc.

In an alternative embodiment, the end-plates are made from rigidmaterials such as biocompatible metal or polymer. In one embodiment, thevariable modulus core may be firmly bonded to the end plates so that theend-plates are incorporated into the mould process and are not separateparts but actually covalently bonded with the core to provide a completedevice. Conversely, the variable modulus core may be located, but notfixed, between the two end-plates to enable the core to slide betweenthe end-plates.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present invention will now be described, by way ofexample only, with reference to the following drawings, in which:

FIG. 1 illustrates a front view of the reactive injection mouldingapparatus that comprises four injection lances;

FIG. 2 illustrates a side view of one of the injection lances of thereaction injection moulding apparatus of FIG. 1;

FIG. 3 illustrates a front view of a PPM apparatus that include lancesand extruder;

FIG. 4 shows a perspective view of an artificial spinal disc accordingto an embodiment of the invention together with endplates above andbelow the disc;

FIG. 5 shows a plan view of the disc shown in FIG. 4;

FIG. 6 shows a cross-sectional view along the line X-X in FIG. 5;

FIG. 7 is a graph showing the relationship between the modulus anddistance through the disc in a radial direction indicated by X-X;

FIG. 8 is a graph showing the relationship between the modulus and thedistance through the disc in a radial direction indicated by Y-Y in FIG.5;

FIG. 9 is a graph showing the relationship between the modulus and thedistance through the disc in an axial direction indicated by Z-Z in FIG.6.

FIGS. 10A, 10B & 10C show the distribution of material properties in amould during the manufacture of an artificial spinal disc according tosome specific examples;

FIG. 11 is a graph to show how a material that has a gradual modulus canbe formed by varying the amounts of two materials injected into a mould,and

FIG. 12 is a graph to show how a material that has a gradual modulus canbe formed by having a step or incremental change in the relative amountsof materials injected into the mould.

DETAILED DESCRIPTION OF EMBODIMENTS

Referring firstly to FIG. 4, there is shown an artificial disc 1together with a pair of end plates 2 used in conjunction with the disc1. The disc 1 is a single unitary component having a soft elastomericcore region that mimics the function of the natural spinal disc nucleusand varies in volume by the total elastomer volume, and a peripheralregion surrounding the core region exhibiting a graded modulus structurein which the modulus increases as a function of the distance from thenucleus region or decreases as a function of the distance from thesurface of the disc 1. It will be appreciated that changing the relativevolume of nucleus and annulus regions alter the overall mechanicalperformance of the complete device. Therefore, the device structure canbe modified to achieve optimum physiological performance.

In the preferred illustrated embodiment, the modulus varies from thesurface of the disc to the nucleus. However, it will also be appreciatedthat the modulus may vary for only a portion of that distance. Althoughreference is made to a disc having a peripheral region and a coreregion, it will be appreciated that these regions are not separate ordiscrete and the disc is formed from one body of material.

FIG. 5 shows a plan view of the spinal disc illustrated in FIG. 4 andFIG. 6 shows a cross-section through the disc along the line marked X-Xin FIG. 5. Both views have been marked with contour lines showing thechange in modulus through the disc, the modulus being greater where thelines lie close together. As can be seen from FIG. 5, the modulusincreases as a function of the distance from the core region in a radialdirection such as the directions indicated by X-X and Y-Y in FIG. 5, andthis is shown in the plots of FIGS. 7 and 8. FIG. 7 illustrates a plotshowing the relationship between the modulus (y-axis) against distancethrough the disc (x-axis). In FIG. 7, this distance is the radialdistance along the line X-X in FIG. 5. In FIG. 8, the distance is theradial distance along the line Y-Y in FIG. 5. FIG. 9 also shows thechange in modulus with respect to the distance through the article in anaxial direction along the line Z-Z in FIG. 6. It can be seen from thesegraphs, that the material of the disc is anisotropic in that the modulusis different depending on the direction of measurement of the modulusthrough the disc.

In FIG. 4, the end plates 2 are shown separated from the disc for thepurpose of the drawing only and are in intimate contact with upper andlower surfaces of the disc respectively when the disc is in use. The endplates 2 are usually bonded to the disc 1. However, they can also beunbonded but in close contact with the disc 1. The end plates 2 areconstructed from any suitable metallic material or alloy that possessessufficient stiffness to contain the disc and suitable fatigue strengthfor that purpose. In other embodiments, the end plates 2 may be providedwith a structured surface with channels and bores suitable to promotebone ingrowth. The end plates 2 may also be coated with anosteoconductive ceramic such as hydroxy apatite. In a preferredembodiment the end-plates are formed as part of the complete device suchthat the end-plates are covalently bonded with the core. Thus, there isa change in modulus between the end-plates and core region See FIG. 6 inwhich the incorporated end-plates are labelled ‘X’.

A disc 1 having the properties described above exhibits responses tocompression and compression-torsion testing under simulatedbiomechanical loads that are similar to those exhibited by the naturalspinal disc during movement of a human being and has mechanicalproperties (force penetration, recovery, creep) that ensures that thedisc and the end plates deliver physiological appropriate motion(flexion, extension and torsion) to the adjacent vertebrae similar tothose of a healthy spinal disc.

Although in a preferred embodiment the polymer product made using themethod of the invention is an artificial spinal disc, it is envisagedthat other devices or components for medical use could also be formedusing one or other of the methods of the invention. One particularcomponent is a variable modulus bearing surface that would replace atleast a portion of damaged or degenerate articular cartilage within asynovial joint. This may include replacement of part of the adjacentbone to provide a reconstructed bearing surface. Examples include, butare not restricted to, an acetabular cup for use in hip arthroplastyprocedures and a bearing surface to replace worn cartilage on the tibialplateau for arthroplasty procedures of the knee. These variable modulusbearing surfaces provide cushioning to the joint and increasescongruency between articular surfaces during load bearing resulting inimproved stress distribution and reduced contact stresses that willimprove the fatigue life of the implant.

It is also envisaged that a variable modulus polymer could be used toreplace or provide additional support to a complete bone or part of abone in surgical procedures carried out for cosmetic as well as medicalreasons.

An alternative embodiment for use in the medical industry is in themanufacture of an intravenous or urethral catheter which must have therequired degree of stiffness to enable it to be passed through bodilyconduits to reach the site of an occlusion but at the same time beflexible enough to prevent unnecessary trauma or collateral injury tothe patient during an invasive procedure. It is envisaged that at leasta portion of the elongate catheter may be formed from material having agradual variation in modulus along its length.

The PPM process will now be described followed by an explanation of itsapplication to the manufacture of a polymer product which exhibits agradual variation in modulus.

The PPM process comprises reacting a multifunctional isocyanate, apolyol and, optionally, a chain extender, wherein at least two reagentsselected from the isocyanate, the polyol, the chain extender, anymixture thereof and any pre-polymer formed therefrom, are intensivelymixed prior to being reactively extruded, to form a polyurethane havinga predetermined stoichiometry and thermal history. In the context of thepresent invention, the term “polyurethane” is understood to include anypolymer which contains multiple urethane linkages and includes, forexample, polyurethane-ureas. In an embodiment, at least a portion of thepolyol or the chain extender is reacted with the isocyanate prior toextensive mixing, so as to “end-cap” the polyol or the chain extruderwith isocyanate groups, thus facilitating subsequent reaction. In amodified arrangement, at least a portion of the isocyanate is reactedwith the polyol or the chain extender prior to extensive mixing.Preferably, at least a portion of the chain extender is mixed with thepolyol prior to intensive mixing. Advantageously, the process allowsabsolute control of reagent stoichiometry whilst intimate mixing of thereagents at the molecular level allows the manufacture of tailoredlinear polyurethanes of narrow molecular weight distribution or narrowpolydispersity. Moreover, a known and reproducible thermal history canbe imparted to the polymer during synthesis, whilst overall thermaldegredation can be minimised by reducing the number of melt cycles forpolyutethane components. Such a process allows the integratedmanufacture of a polyurethane resin, finished product or aqueouspolyurethane dispersion.

The multifunctional isocyanate may be any suitable aromatic, aliphaticor cycloaliphatic polyisocyanate, but is most preferably an organicdiisocyanate. Preferred organic diisocyanates include4,4′-diisocyanatodiphenylmethane, 2,4′-diisocyanatodiphenylmethane,isophorone diisocyanate, p-phenylene diisocyanate, 2,6-toluenediisocyanate, polyphenyl polymethylene polyisocyanate,1,3-bis(isocyanatomethyl)cyclohexane, 1,4-diisocyanatocyclohexane,1,6-hexamethylene diisocyanate, 1,5-naphthalene diisocyanate,3,3′-dimethyl-4,4′-biphenyl diisocyanate,4,4′-diisocyanatodicyclohexylmethane,2,4′-diisocyanatodicyclohexylmethane, and 2,4-toluene diisocyanate, orcombinations thereof. The polyol may be any suitable polyhydroxycompound, but is generally a hydroxy-terminated ester, ether orcarbonate diol. Preferred polyalkylene ether glycols includepolyethylene ether glycols, poly-1,2-propylene ether glycols,polytetramethylene ether glycols, poly-1,2-dimethylethylene etherglycols, poly-1,2-butylene ether glycol, and polydecamethylene etherglycols. Preferred polyester polyols include polybutylene adipate andpolyethylene terephthalate. Preferred polycarbonate diols includepolytetramethylene carbonate diol, polypentamethylene carbonate diol,polyhexamethylene carbonate diol, polyhexane-1,6-carbonate diol andpoly[1,6-hexyl-1,2-ethyl carbonate]diol. However, many other suitablepolyhydroxy compounds can also be used depending upon the desiredapplication. The polymerisation reaction may be carried out in thepresence of an activating amount of a suitable catalyst, for example, anorganotin catalyst such as stannous octanoate. However, the presence ofa catalyst is not usually necessary, due at least in part to theefficiency of the intensive mixing step, or even desirable, dependingupon the intended application of the polyurethane, such as, for example,in implantable devices. For some applications, the multifunctionalisocyanate and polyol are not reacted with a chain extender. In mostcases, however, a chain extender will be included to effect chainextension or cross-linking of the urethane-linked pre-polymer as itforms. Any suitable polyol, polythiol or polyamine or mixture thereofthat is suitable for this purpose may be used, such as, for example,mixed diols comprising a 2,4-dialkyl-1,5-pentanediol and a2,2-dialkyl-1,3-propanediol. Specific examples of2,4-dialkyl-1,5-pentanediol include 2,4-dimethyl-1,5-pentanediol,2-ethyl-4-methyl-1,5-pentanediol, 2-methyl-4-propyl-1,5-pentanediol,2,4-diethyl-1,5-pentanediol, 2-ethyl-4-propyl-1,5-pentanediol,2,4-dipropyl-1,5-pentanediol, 2-isoptopyl-4-methyl-1,5-pentanediol,2-ethyl-4-isoptopyl-1,5-pentanediol, 2,4-diisopropyl-1,5-pentanediol,2-isopropyl-4-propyl-1,5-pentanediol, 2,4-dibutyl-1,5-pentanediol,2,4-dipentyl-1,5-pentanediol, 2,4-dihexyl-1,5-pentanediol, and the like.Specific examples of 2,2-dialkyl-1,3-propanediol include2,2-dipentyl-1,3-propanediol, 2,2-dihexyl-1,3-propanediol and the like.Especially preferred chain extenders include 1,4-butanediol,1,2-ethylene diamine, hydrazine and triethylamine. However, many othersuitable classes of polyols and amines are known to those skilled in theart are also included. In the context of the present invention, thephrase “intensively mixed” generally means that the two or more reagentsselected from the isocyanate, the polyol, the chain extender, anymixture thereof and any pre-polymer formed therefrom, are intimatelymixed at the molecular level. In a preferred embodiment, the two or morereagents are intensively mixed by vortexing, such that two or morereagent streams are caused to coincide and flow together in a spiralfashion. In another embodiment, the two or more reagents are transportedvia a swash plate pump or a gear pump. Most preferably, the two or morereagents are intensively mixed via a reactive injection processingtechnique, of the kind used in conventional RIM or SRIM processes. In apreferred embodiment, the synthesis technique of the current inventionutilises an impingement mixing head, similar to those used in a RIMmachine, and fitted with two or more reagent streams. Each differentstream can be programmed to deliver the required amount of reagentcontinuously and with high accuracy not associated with current RIM orREX techniques. Moreover, as the reagents are intensively mixed at amolecular level, the reaction generally starts spontaneously, therebyavoiding the need for inclusion of reaction catalysts altogether orgreatly reducing the amounts of such catalysts required. Since many ofthe catalysts normally used in such reactions are potentially highlytoxic in vivo, the inventive process is particularly suitable for makingpolyurethane medical devices intended for implantation. The mix-head ispreferably self-cleaning, to avoid having to clean the apparatus aftereach used. In an embodiment, the two or more reagents are delivered tothe mix-head under pressure, preferably via one or more injectionlances. For example, a first injection lance may contain isocyanate anda second injection lance may contain polyol and chain extender, or afirst injection lance may contain a first isocyanate, a second injectionlance may contain a second isocyanate mixed with an aliquot of a firstpolyol to effect end-capping, a third injection lance may contain asecond polyol and a fourth injection lance may contain a chain extender.There are clearly many possible combinations and permutations of thevarious reagents and all of these combinations are intended to beincluded within the scope of the present invention. Preferably, themixing step is substantially instantaneous, most preferably occurringwithin a time period of fraction of a second to a few seconds at most.It is especially desirable that the resultant mixture is substantiallyhomogeneous immediately after mixing, although the subsequentcomposition of the mixture will obviously change as polymerisationproceeds. In the context of the present invention, the term “reactivelyextruded” is understood to mean that the physical and chemicalproperties of the polyurethane mixture are modified in a continuous flowstirred tank reactor (CSTR) or an extruder, preferably by at least oneof the various forms of modification described above in relation toconventional REX procedures.

The resultant mixture may be fed directly into an extruder, the latterpreferably being close coupled to the mix-head. The extruder may beimmediately adjacent to and is, preferably, directly connected to themix-head, such that the resultant polyurethane pre-polymer mixtureexiting the mix-head passes straight into the extruder. The mixture maybe fed into an extruder via a rheometer, a densitometer, aspectrophotometer or any combination thereof. This permits aninstantaneous “snapshot” of the viscosity, density or composition of thereaction mixture to be taken before the reactive extrusion processbegins and allows for any adjustments thereto to be made. Alternatively,the resultant mixture is fed into the extruder via a reaction chamber,preferably, a stirred reaction chamber, to allow further polymerizationreactions to occur. Preferably, the mixture is fed into the extruder ata rate of 0.01-25 kg/s, preferably 0.1-10 kg/s, and most preferably 1-5kg/s. The role of the extruder is essentially two fold. Firstly, thetemperature of sections along the length of the extruder can becontrolled, thereby controlling reaction temperature, which in turndictates the progress of the polymerisation reaction. Secondly, aspolymerisation reactions are taking place in the extruder, additionalreagents can be introduced at the extruder and can participate in thepolymerisation reaction to give modified polyurethanes of specificvalue, such as polyurethanes where the end group is different from thegroups within the polymer chain. For example, a chain extender can bemixed with the pre-polymer at this stage, to promote chain extension orcross-linking and increase viscosity and molecular weight. Sensors canbe placed along the length of the extruder barrel to monitor thereaction as it progresses, whilst temperature control means can be usedto ensure that the reaction processes occur within defined temperatureranges. In a preferred embodiment, therefore, the polyurethane can bemade to undergo thermal profiling during the reactive extrusion process,such that it has a well-defined thermal history. The extruder may alsocomprise a rheometer, a densitometer, a spectrophotometer or anycombination thereof at a pre-determined point along its length or at itsexit, such that the physical and chemical properties of the formingpolymer and the final polyurethane can be closely monitored and, ifnecessary, adjusted during the reactive extrusion process.

It is also known to provide an apparatus for making a polyurethane usingthe PPM process comprising: a delivery system for quantitativelydispensing at least two reagents selected from an isocyanate, a polyol,a chain extender, any mixture thereof and any pre-polymer formedtherefrom; mixing means for intensively mixing said at least tworeagents; and reactive extrusion means. The delivery system comprisesone or more injection lances, preferably controlled by the use of lineartransducers. The reactive extrusion means comprises a barrel extruder,preferably having one or more entry ports for introduction of variousreagents. Preferably, the reactive extrusion means is a twin screwextruder, most preferably a co-rotating twin screw extruder. Anycommercially available twin screw extruder may be used, such as an APVBaker MP2030 with a 30 mm screw diameter (L:D=40/1; D=30 mm) co-rotatingtwin screws and sixteen heating zones, which is available from APVBaker, Speedwell Road, Parkhouse East, Newcastle-under-Lyme, UnitedKingdom. The extruder can be provided with at least one thermocouple, tomonitor the temperature of extruded material in the immediate vicinityof the thermocouple. The extruder may also be provided with temperatureregulating means, to control the temperature of the extruded material inthe region adjacent thereto and the apparatus may include measurementmeans adapted to measure a physical or chemical parameter or property ofthe polyurethane mixture. Preferably, the measurement means comprise arheometer, a densitometer, a spectrophotometer or any combinationthereof located between the mixing means and the reactive extrusionmeans, so as to enable an instantaneous assessment of the properties ofthe polyurethane or pre-polymer mixture to be made, prior to teactiveextrusion. The apparatus also comprises at least one measurement meanswithin or at the exit of the reactive extrusion means to monitor theproperties of the polyurethane mixture and the final polymer. Theapparatus may further comprise: means for controlling the rate at whichthe delivery means dispenses said at least two reagents in response to afirst control signal; means for controlling the rate at which theresultant mixture is fed to the reactive extrusion means in response toa second control signal; means for controlling the temperature of thepolyurethane mixture in the reactive extrusion means in response to athird control signal; means for detecting a property of the polyurethanemixture during reactive extrusion and being adapted to generate adetector signal; and a processor adapted to generate said first, secondand third control signals in response to said detector signal. Thisenables the inventive process to be automated and any necessaryadjustments required to produce a polyurethane of well defined orpre-determined stoichiometry and thermal history to be accuratelycontrolled. In this last mentioned embodiment, the control and detectionmeans are preferably programmable means, such that their operation canbe controlled by a program run on a computer.

The PPM apparatus 3 is illustrated in FIG. 1 and comprises fourinjection lances 5, a four reagent stream mix head 6 and a mould 7. Itwill be appreciated that the process is not limited to the use of 4lances and that there may be 5 or 6 or more depending on the number ofmaterials to be manufactured. This means that more than just twopolyurethanes with different stiochiometries can be made and mixedtogether to get a more complex variable modulus product. It will beappreciated that may involve more than just two intermediate vessels.

Each lance 5 is numbered for ease of identification and comprises ahydraulic cylinder 8, a lance pump 9, an inlet pipe 10, a non-returnvalve 11 and an outlet pipe 13. The mix head 6 is adapted so that bothpairs of reagent streams from the four outlet pipes 13 directly opposeeach other. The mix head 6 comprises a cylindrical mix-pin 14 havingfour vertical grooves (not shown) that are inscribed into the surface ofthe cylinder at equal intervals and run along ⅜ths of its length fromthe mid point to within ⅛^(th) of its length from the bottom face of thepin 14.

Referring to FIG. 2, each lance 5 is supplied with reagent from mix tank15 which is stirred by a paddle stirrer 16. Reagent is supplied to lance5 via inlet pipe 10, passing through non-return valve 11. Reagent isdrawn from mix-tank 15 into lance 5 by raising lance pump 9 andsubsequently ejected from lance 5 by depression of lance pump 9 throughthe action of hydraulic cylinder 8 controlled by means of a lineartransducer 17 controlled by means of a personal computer (not shown).Reagent is supplied to mix-head 6 via outlet pipes 13. When mix pin 10is fully inserted into mix head 6, the grooves align with the outletpipes 9 to provide channels to the return pipes 18, such that thereagent streams are recycled to mix-tanks 15 without being able to enterthe mould 7. When mix-pin 10 is retracted so that its lower face sitsbetween outlet pipes 13 and the return pipes 18, the reagents areimpingement mixed before passing into mould 7. When mould 7 is full, mixpin 10 is again fully inserted allowing excess reagents to be recycledto mix tanks 15 via return pipes 18.

FIG. 3 illustrates the complete PPM manufacturing apparatus thatcomprises four injection lances 5, a mix head 6 and an extruder 18. Theextruder 18 is joined to the mix head 6 via a rheometer 19 and has 30 mmdiameter co-rotating twin screws (not shown), sixteen programmableheating zones 20, a second rheometer 21 and a die 22. It will beappreciated that alternative forms of extruders can also be useddepending on the application. When mix pin is retracted, mixed reagentsfrom mix head pass via rheometer 19 into the extruder 18. Reactionmixture passes through each of the heating zones 20 which are programmedto maintain the mixture at a predetermined temperature before exitingthe extruder 18.

In a typical run, the mix-tanks are pre-heated to the requiredtemperature and then charged with the required amount of reagents, asdetermined by the stoichiometry, sequence distribution requirements andlength of production run required. The reagents are continuously stirredby paddle stirrers under nitrogen until homogenous and at constanttemperature. A “dry” run is carried out (where the mix-head pin is notretracted) under the required reaction conditions, that is, streammix-ratios, mix-volume and mix-time. The pressure of each stream ismonitored during this run. The pressure in each stream can be balancedif necessary by adjustment of a needle valve behind the mix-head orifice(not shown). Balancing the pressure of each stream is essential, as itfacilitates good mixing as well as preventing the reaction from takingplace in the supply lines, which will occur if the pressure of onestream is significantly greater than the other streams, thereby fillingthe stream feed line. The reagents in each tank are circulated using thelances, with the lances drawing the reagents from the holding tank andejecting them around the circuit and back into the holding tank. Whenready to run, the control software is launched. The size (volume) ofeach lance is programmed into the software, and can be changed ifrequired. Several pieces of information are requested by the software,namely: streams to be used, mix-volume, mix-time, and mix-ratio. The“streams to be used” information activates the required lances. Themix-volume is the total amount of product required at the end of therun, with the maximum volume being the sum of the selected streamvolumes. The mix-time determines the time that the mix-pin is retractedand the velocity of the lances. The mix ratio determines the ratio ofthe velocities of the lances. From this information, the softwarecalculates the ideal dispensing requirements. For example, using thefollowing parameters for 2 lances of equal size, 1 L mix-volume, 4seconds mix-time and a mix-ratio of 1:1, 0.5 L from each stream is mixedover a period of 4 seconds. If a mix-ratio of 3:1 were required, 0.75 Lof the first stream would be impingement mixed with 0.25 L of the secondstream (with the velocity of the first stream being three times that ofthe second stream). The software becomes invaluable when using morestreams of different sizes and different mix-ratios. The position ofeach lance is measured with the linear transducer. After the aboveinformation is entered into the software, the contents of the lances areejected and the “empty” reading from the transducers taken. The lancesare then filled completely, and the “full” reading taken.

When the apparatus is ready to run, the lances 5 eject reagents into therespective transfer lines. The velocity of each lance 5 is monitored bysoftware and, when constant, the mix pin 14 is retracted allowingimpingement mixing of the reagents in the mix head 6. The mixed reagentsundergo rapid polymerisation reactions as they pass from the mix head 6into the close coupled twin screw extruder via an in-line rheometer 19.The reacting mixture passes through the extruder 18 in a predeterminedtime and follows a predetermined thermal profile dictated by thecombination of the running speed of the extruder 18 and the temperaturesettings of each of the programmed temperature zones 20. An in-linerheometer 21 is fitted at the output end of the extruder 18 to give realtime measurement of theological properties which are used as a signal tocontrol aspects of the operation of the process, such as extruder speed,temperature of the extruder zones, lance speed, stoichiometry, reagenttemperature, in accordance with an algorithm operated by a computer, togive real time control of the theological properties of thepolyurethane.

A product having a gradual variation in modulus is produced according toone embodiment of the invention by forming two polyurethanes each havinga different stoichiometry and/or thermal history and formed either oneafter the other using the same PPM machine or, simultaneously using twoseparate PPM machines. If the polyurethanes so produced are intensivelymixed prior to injection into a mould, or are injected separately intothe mould so that they mix within it prior to completion of thepolymerisation reactions taking place, the reactions will continuebetween the two polyurethanes once in the mould resulting in a productexhibiting a variation in modulus through it. The polyurethanes formedusing the same or different machines may be stored in an intermediatevessel prior to injection into the mould. If the same machine is beingused to produce both polyurethanes, the first polyurethane may be storedin an intermediate vessel whilst the second polyurethane is formed byperturbing the relative amounts of the reagents to change thestoichiometry of the polyurethane emerging from the machine. The secondpolyurethane may be injected directly into the mould together with thefirst polyurethane from the intermediate vessel. Alternatively, thesecond polyurethane may be stored in another intermediate vessel so thatboth polyurethanes may be injected into the mould from their respectivevessels. The temperature of each vessel may be independently controlledto impart a different thermal history and/or viscosity to each of thepolyurethanes stored in the intermediate vessels. As already mentionedabove, each of the polyurethanes can be fed through an extruder havingindependently controllable temperature sections do that the reactiontemperature and hence the progress of the polymerisation can becontrolled. The polyurethane can also be made to undergo thermalprofiling during the reactive extrusion process such that it has a welldefined thermal history.

Of particular interest to the Applicants lies in the evaluation of theflow of reacting polyurethane systems into a three-dimensional (3-D)mould cavity that is suitable for the manufacture of spinal discprostheses. Consequently, the aim is to provide accurate 3-D placementof material within the moulding cavity with the ideal result being aperipheral (annulus) material surrounding a central core (nucleus)region with the nucleus material being symmetrical from the mid-point onthe vertical plane but with a significant lateral distribution, as hasalready been described with reference to FIGS. 2 to 6. Severalparameters which affect this distribution are outlined below:

-   -   1. Material properties—viscosity, contact angle of the material.    -   2. Injection Speed—With reference to a spinal disc, the        injection speed of annulus and nucleus materials are different        to achieve the correct distribution.    -   3. Injection port geometry—this will influence the flow of        material into the mould. With reference to a spinal disc,        injection port geometry will influence the distribution of the        nucleus material.

Many of these parameters can be varied to achieve optimum conditions forthe control of the 3-D distribution of materials within a mould. Forexample, material viscosity can be influenced by the temperature of themould and/or intermediate vessel, injection rate is determined by thedispense rate from the intermediate vessel and an optimum injection portgeometry can be machined to provide the desired conditions. In contrast,the contact angle is dependent upon the properties of the injectedmaterial and the material used to manufactured the mould e.g. aluminium,steel etc. Furthermore, a commercially available release agent e.g.silicone, will also influence the interaction between injected materialand mould walls. Understanding the influence of the contact angle willenable the injection rate and injection port geometry to be modifiedaccordingly to achieve the desired 3-D distribution of materialproperties.

Several examples of how these parameters influence the 3-D distributionof material properties within a mould for the manufacture of variablemodulus device such as an artificial spinal disc prostheses will now begiven.

An axisymmetric finite element (FE) model of a flat mould (10 mm height,20 mm radius) was constructed and validated experimentally using mouldswith the same geometry and volume. The following parameters were used(values given are approximate):

Viscosity Material A=5000 cP

Viscosity Material B=15000 cP

Contact angle of material with mould surface=60 degrees.

Injection Speeds=0.100 ml/s and 0.010 ml/s

For the purpose of this first example, Material ‘A’ will from theannulus and Material ‘B’ will form the nucleus and the injection ratewill be altered to illustrate the change in 3-D distribution of materialwithin the mould. The resulting distribution of material propertiesusing a constant injection rate of 0.010 ml/s and 0.100 ml/s areillustrated in FIG. 10A/Table 1 and FIG. 10B/Table 2 respectively. Theannulus and nucleus regions are indicated in the diagrams together withan intermediate region that exhibits a variation in modulus between thenucleus and annulus properties. For the purpose of this example thevariation in modulus is generated by interfacial mixing within theinjection port prior to the bulk flow reaching the mould (not shown inthis example).

TABLE 1 Nucleus Viscosity Annulus Injection Speed Contact Angle (cP)Viscosity (cP) (ml/s) (Degree) 15000 5000 0.010 60

TABLE 2 Nucleus Viscosity Annulus Injection Speed Contact Angle (cP)Viscosity (cP) (ml/s) (Degree) 15000 5000 0.100 60

It is clear from the illustrations that a low nucleus injection speedprovides a nucleus region that is located lower in the mould (FIG. 10A)whereas higher injection speeds provide a nucleus region located at thetop of the mould (FIG. 10B). It will be appreciated that an optimumspeed for a given mould geometry and material properties will provide aproduct that exhibits symmetry in the vertical plane. Furthermore,injection rate will also determine the distribution of materialproperties in a radial direction. For the example provided, slowerinjection speeds provide a nucleus material that exhibits a greaterradial distribution compared to higher injection speeds. With referenceto a spinal disc, optimisation of the injection speed for annulus andnucleus materials would provide a nucleus material that is located atthe centre of the mould encapsulated by annulus material. In the sameway, the distribution of material that exhibits a gradual variation inmodulus between annulus and nucleus regions can also be preciselycontrolled.

It will be appreciated that the extent of material distribution withinthe product will also be influenced by mould geometry, injection portgeometry and material properties and the injection rate should bemodified accordingly to achieve the desired material distribution.

A further example using the same model demonstrates the influence ofnucleus and annulus material properties. FIG. 10C and Table 3illustrates the distribution of material properties in a mould thatconsists of a nucleus (Material ‘A’) and annulus (Material ‘B’) andresults from using an injection speed that is equivalent to that used inFIG. 10B. It will be appreciated that despite the vertical momentumprovided by the bulk flow of material through the injection port, thelower viscosity nucleus is unable to penetrate through the highviscosity annulus material at the surface. Consequently, the nucleusmaterial is distributed in a radial direction to provide a nucleusregion that exhibits greater vertical and radial symmetry in comparisonto the material distribution illustrated in FIG. 10B.

TABLE 3 Nucleus Viscosity Annulus Injection Speed Contact Angle (cP)Viscosity (cP) (ml/s) (Degree) 5000 15000 0.100 60

It will be appreciated from the foregoing examples that the manufactureof a variable modulus product requires precise control of the speed ofmaterial delivery; particularly when fabricating devices or componentswith a relatively small volume such as a spinal disc prosthesis.

Whilst the example provided describes the distribution of propertieswithin a mould suitable for the manufacture of variable modulusprostheses, the same principles and inventive technology are applicableto other mould geometries and variable modulus products that requireaccurate 3-D placement of the material.

The following section provides some more detail of how a variation inmodulus can be achieved as a result of varying the relativecontributions of different materials from two intermediate vessels.

Manufacture of a device that exhibits a gradual variation in modulusfrom one material (A) to another (B) can be achieved by varying therelative amounts of materials dispensed from the intermediate vessels.An example of this process is represented by the graph of FIG. 11 inwhich the Y-axis is the percentage of material and the X-axis is thetime. At the start of the injection process only material A (solid line)is injected into the mould. After a given time, injection of material Ais retarded whilst the injection of material B (dashed line) begins suchthat the relative amounts of both materials is continuously varied.Alternatively, the variation in modulus between two or more materialsmay be generated by having a step or incremental change in the relativeamounts of materials injected into the mould as represented in the graphof FIG. 12.

It will be appreciated that the extent of the region of graduatedmodulus will be governed by the rate at which the injection of materialsA and B are varied.

With reference to the manufacture of a spinal disc, material A isinjected first to form the annulus. Injection of material A is thenretarded as the flow of material B is increased to generate a variationin material properties prior to injection of 100% of material B to formthe nucleus region of the spinal disc. Manufacturing parametersdescribed above are optimised for the spinal disc mould geometry andmaterial properties and a suitable injection speed for annulus andnucleus materials chosen accordingly to provide the desired 3-Ddistribution of material properties within the mould.

In the method, known as step perturbation, the relative amounts of theat least two reagents are perturbed during the course of the reaction soas to continuously vary the modulus of the polyurethane so formed. Thepolyurethane is then injected into a mould defining the polymericproduct.

In another proposed method, the output from the reaction injectionmoulding machine may be continuous and of a fixed composition. However,the PPM process may include an extruder through which the polymer ispassed. The extruder may be provided with multiple ports along itslength and mould may be filled with material sampled from each port. Thematerial from each port may be processed differently to providematerials that possess a different modulus. A layer of material fromeach port is then fed into the mould and the layers diffuse into eachother to provide a final component having a variable modulus. Thecomponent may also undergo a post compression stage at high temperatureto form the final product and increase the degree of diffusion of thelayers into each other to provide a product having a more gradual changein modulus.

In accordance with the methods of the invention, a region that exhibitsa variation in modulus between the two materials can arise throughseveral processes. First, as mentioned previously, materials areinjected one after the other and a variation in modulus arises throughinterfacial mixing between the materials. Second, materials are injectedthrough a common injection port that allows interfacial mixing withinthe injection tube prior to flow reaching the mould. In this regard, theextent of the graded modulus may be modified according to the length ofthe injection nozzle which determines the extent of mixing betweenmaterials prior to the flow entering the mould. An alternative methodinvolves passing continuously varied amounts of each material through astatic mixer or length of tube, to achieve a resultant material thatexhibits a continual change in properties. This method relies uponprecise control of the material dispense cylinders to achieve avariation in the relative amount of material dispensed from eachdelivery stream.

Alternatively, the intermediate vessel may be a mould or carousel. Theintermediate vessel is maintained at adequate temperature and thematerial reacts to form a slug. At the required moment this slug can beinjected into a cavity mould having the shape of the required component.As the material is held in the carousel, it enables the reactant toconsolidate and a known thermal history to be imparted into the product.

These materials may be produced using one PPM machine that switchesbetween the manufacture of different materials to maintain the level ofmaterial contained within the dispense cylinders. However, these methodsare not confined to use with a single PPM or Reaction Injection Mouldingmachines. Alternatively, if larger flow rates are required, two PPMmachines maybe employed to manufacture each material separately toensure a continual flow of materials into the dispense cylinders. Itwill be appreciated that other material manufacturing methods orarrangements of the PPM apparatus could be used to feed the dispensecylinders to enable manufacture of devices and components that exhibit avariation in modulus.

The intermediate vessel may alternatively be an injection mouldingmachine barrel or syringe. The material may then be injected directlyinto the required mould.

Many modifications and variations of the invention will be apparent tothose skilled in the art and the foregoing description should beregarded as a description of the preferred embodiments only.

1. A process for making a polymeric product having a gradual variationin modulus through at least a portion of the product, comprising thesteps of: (a) reacting at least one of a multifunctional isocyanate, apolyol and a chain extender, wherein at least two reagents selected fromthe isocyanate, the polyol, the chain extender, any mixture thereof andany pre-polymer formed therefrom, are intensively mixed to form a firstpolyurethane having a predetermined stoichiometry and thermal history;(b) reacting at least one of a multifunctional isocyanate, a polyol anda chain extender, wherein at least two reagents selected from theisocyanate, the polyol, the chain extender, any mixture thereof and anypre-polymer formed therefrom, are intensively mixed to form a secondpolyurethane having a predetermined stoichiometry and thermal historywhich is different to the stoichiometry and thermal history of the firstpolyurethane; and (c) injecting the first and second polyurethanes intoa mould defining the polymeric product before the polymerizationreactions associated with the production of the first and secondpolyurethanes are complete so that polymerization reactions between thefirst and second polyurethanes occur in the mould to form a region ofpolyurethane having a gradual variation in modulus, wherein the regionextends through at least a portion of the product.
 2. A processaccording to claim 1, comprising the step of injecting the first andsecond polyurethanes into the mould simultaneously.
 3. A processaccording to claim 2, comprising the step of altering the relative rateof injection of the first polyurethane into the mould relative to therate of injection of the second polyurethane into the mould.
 4. Aprocess according to claim 1, including the step of mixing the first andsecond polyurethanes prior to injection into the mould via a commoninjection port.
 5. A process according to claim 4, including the step ofaltering the length of the common injection port to control the degreeof mixing of the first and second polyurethanes prior to injection intothe mould.
 6. A process according to claim 1, including the step ofcontrolling the relative amounts of the first and second polyurethanesinjected into the mould.
 7. A process according to claim 6, includingthe step of injecting the same amount of the first and secondpolyurethanes in to the mould.
 8. A process according to claim 1,wherein the method includes the step of forming the first and secondpolyurethanes simultaneously in a separate apparatus.
 9. A processaccording to claim 1, wherein the method includes the step of formingthe first and second polyurethanes using the same apparatus, the methodcomprising the steps of forming the first polyurethane and subsequentlyperturbing the relative amounts of the reagents to form the secondpolyurethane.
 10. A process according to claim 9, including the step ofpassing the first polyurethane into an intermediate vessel beforeformation of the second polyurethane.
 11. A process according to claim10, wherein the method includes the step of passing the secondpolyurethane into an intermediate vessel.
 12. A process according toclaim 11, including the step of simultaneously injecting the first andsecond polyurethanes into the mould from said intermediate vessels. 13.A process according to claim 12, including the step of injecting thefirst and second polyurethanes into the mould at different injectionrates.
 14. A process according to claim 13, wherein the method includesthe step of controlling the temperature of at least one of theintermediate vessels to impart at least one of a different stoichiometryand thermal history to the first and second polyurethanes containedherein.
 15. A process according to claim 1, wherein the gradualvariation in modulus varies substantially linearly through the region.